Alternative Therapies for Orthotopic Heart Transplantation Daniel J. Garry, M.D., Ph.D. Medical Grand Rounds, Department of Internal Medicine July 19, 2001 Disclosure: This is to acknowledge that Daniel Garry, M.D., Ph.D. has not disclosed any financial interests or other relationships with commercial concerns related directly or indirectly to this program. Dr. Garry will be discussing off-label uses in his presentation. BIOGRAPHICAL INFORMATION: Daniel J. Garry, M.D., Ph.D. Assistant Professor, Departments of Internal Medicine, Molecular Biology UT Southwestern Medical Center INTERESTS: Congestive Heart Failure/Cardiac Transplantation Basic science mechanisms·of stem cell biology & oxygen metabolism 2 Congestive heart failure (CHF) Therapeutic strategies for heart failure have evolved tremendously over the past several hundred years. Treatment of congestive heart failure (CHF) or what was referred to as "dropsy" was aimed initially at restoring a balance of fundamental elements and humors. In 1683, Thomas Sydenham recommended bleeding, purges, blistering, garlic and wine. Additional treatments were attempted and abandoned after unrewarding anecdotal experiences (i.e. death). Progress regarding the treatment of heart failure was evident with the introduction of amyl nitrate, mercurial diuretics, digitalis glycosides and bed rest in the early 20th century. Medical therapy for heart failure in the 1960's included digitalis, thiazide diuretics (introduced in 1962) and furosemide (introduced in 1965). The utilization of vasodilators for heart failure were implemented in the 1970's (nitroprusside in 1974 and hydralazine in 1977) and the first large, randomized, clinical trial for heart failure was not completed until 1986 (V-HeFf 1). Since then, the design and completion of a number of large, randomized, placebo-controlled clinical trials have established angiotensin-converting enzyme inhibitors and B-adrenergic receptor antagonists as the cornerstones of therapy. The following table is provided as a summary of these trials. Table 1: Clinical trials for heart failure management #of CHFTrials Treatment NYHA Class Outcome Reference Pts ACE·I&ARB Ram ipril vs placebo in CHF A IRE Not available Improved survival with ramipril I post-MI 2006 Low dose vs high dose .!. combined end· point (mortality & ATLAS lllliiiJV 3164 2 lisinopril hospitalization) with high dose lisinopril Captopril Captopril superior to placebo for exercise Captopril vs placebo IIIIII 92 3 Multicenter tolerance CONSENSUS-I Enalapril vs placebo IV 253 ,J. mortality and morbidity with enalapril 4 J. mortality and hospitalization rate with ELITE Losartan vs captopril 11/lliiiV 722 5 losartan Losartan equal to captopril for mortality but ELITE· II Losartan vs captopril li/111/lV 3152 6 better tolerated lmidapril (high & low dose) i excerise capacity and ,J. ANP/BNP levels lmidnpril in CHF !IIIII 244 7 vs placebo with high dose imidapril Sustained hemodynamic benefit and J. lrbesartan in CHF lrbesartan at various doses IUlli/IV 218 8 worsening of CHF at high dose of irbesartan Similar clinical outcomes between low dose NETWORK Enalapril at various doses Illlli/IV 1532 9 and high dose enalapril Candesartan vs cnalapril vs Combination treatment with J.. LV dilation RESOLVD II/III/IV 768 10 combination but no change in mortality or morbidity RESOLVD Metoprolol CR vs placebo i LV function and .!. mortality with IUUI/IV 426 II (Metoprolol Study) with ACE! and/or ARB metoprolol CR in all groups J, mortality and morbidity with captopril in SAVE Capotpril vs .placebo I 2231 pts with asymptomatic LV dysfunction post- 12 Ml SOLVD-T Enalapril vs placebo li/111 2569 ,J. mortality and morbidity with enalapril 13 SOLVD-P Enalapril vs placebo 1111 4228 Enalapril delaved Sx's ofCHF 14 T exercise capacity and J.. morbidity with STRETCH Candesartan vs placebo llllll 844 15 candesartan Aldactone Receptor Antagonist ! mortality and morbidity with RALES Spironolactone vs placebo III/IV 822 16 spironolactone 3 Antl-Arrhtbymlc Drugs J.. mortality and hospitalization mte with Amiodarone in CHF Amiodarone vs placebo Not available 674 17 amiodarone in non·ischemic cardiomyopathy &PVCs No change in mortality and J. hospitalization Diamond-CHF Dofetilide vs placebo Ili/JV 1518 with dofetilide; Also better at converting AF 18 and maintaining sinus GESICA Amiodarone vs placebo II/JII/JV 516 .!. mortality and morbidity with amiodarone 19 Jl_-Blockers ANZTrial Carvedilol vs placebo II/II! 415 .J, morbidity and mortality with carvedilol 20 Similar mortality rates with both bucindolol BEST Bucindolol vs placebo IIJJIV 2708 21 and placebo J. all cause mortality with carvedilol in post- CAPRICORN Carvedilol vs placebo Not available 1959 22 MI pts with LV dysfunction COPERNICUS Carvedilol vs placebo Ili/JV 2289 J. morbidity and mortality with carvedilol 23 ! morbidity with bisoprolol but no change CIBIS-1 Bisoprolol vs placebo Ili/JV 641 24 on mortality J. mortality and hospitalization rate with CilliS-U Bisoprolol vs placebo IIJJIV 2647 25 bisoprolol Carvedilol CHF Carvedilol vs placebo 11/lll 1094 .J. morbidity and mortality with carvedilol 26 Study_ J. morbidity with metoprolol but no MDC Metoprolol vs placebo II/III 383 27 difference in mortality Metoprolol CRIXL vs MERIT-HF II/III/IV 3991 .J. morbidity with metoprolol CRIXL 28 placebo MEXIS Metoprolol vs xamoterol IIIli) 210 T LV dysfunction with xamoterol 29 .J. mortality and hospitalization rate with MOCHA Carvedilol vs placebo 11/Jil 345 30 carvedilol PRECISE Carvedilol vs placebo IJJI!l 278 .!. morbidity with carvedilol 31 US Carvedilol CHF J. morbidity and mortality with carvedilol in Carvedilol vs placebo ([ 366 32 Study mildCHF Positive Inotropic DrullS J. morbidity but no change in mortality with DIG Trial Digoxin vs placebo 1/11/JII 7788 33 die.oxin T exercise capacity and clinical status with Milrinone·Digoxin Milrinone vs digoxin vs IIIli I 230 digoxin and f ventricular arrhythmias with 34 Trial combination vs placebo milrinone T exercise capacity but also T mortality with PICO Pimobendan vs placebo 11/lll 317 35 pimobendan PRIME-I! Jbopamine vs placebo III/IV 1906 T mortality with ibopamine 36 PROMISE Milrinone vs placebo III/IV 1088 T mortality and morbidity with milrinone 37 PROVED Di2oxin vs placebo II/III 88 Worsenin2 CHF with di2oxin withdrawal 38 RADIANCE Di2oxin vs placebo 11/Jli 178 Worsenin2 CHF with di2oxin withdrawal 39 VEST Vesnarinone vs placebo III/IV 3833 Dose dependent T mortality with vesnarinone 40 Xarnoterol Trial Xamoterol vs placebo III/IV 516 T mortality with xamoterol 41 Vasodilators J. morbidity with diltiazem but no change in DiDi Diltiazem vs placebo Not available 186 42 mortality New onset or worsening CHF with diltiazem MDPT Diltiazem vs placebo Not available 623 43 in post-MI pts Equal mortality and morbidity rates with PRAISE Amlodipine vs placebo IIJJIV 1153 44 amlodipine and placebo REFLECT Flosequinan vs placebo II/III 193 .!. morbidity with flosequinan + ACEI 45 Flosequinan + ACEI vs FACET Not Available 322 .J. morbidity with flosequinan + ACEI 46 ACEI+ pl acebo V-HeFT-I H+l vs p_razosin vsj!lacebo IJJIII 642 .J. mortality with H+I 47 V-HeFT-II H+l vs enalaoril 11/lll 804 Enalapril superior to H+l for survival 48 Felodipine + enalapril vs No difference in mortality between treatment V-HeFT-III Not available 450 49 enalapril +placebo 2rDUOS 4 Therefore, the goals for effective management of cardiomyopathy include the treatment to prevent or delay the progression ofleft ventricular dysfunction (i.e. congestive heart failure) and are focussed on the relief of symptoms as well as the cellular and molecular modulation of the cardiomyocyte (remodeling). The current treatment strategy (2001) includes the following pharmacological agents (50-53): • ACE inhibitors (enalopril, captopril, etc.) • 13-blocker therapy (carvedilol, metoprolol) • Digoxin • Diuretics (lasix and spironolactone) • Vasodilator agents (hydralazine and nitrates) Establishing a hierarchy of advanced heart failure Heart failure is a deadly disease and accounts for more than 250,000 deaths in the U.S. each year. In advanced heart failure, the estimated survival is frequently used to influence a specific therapeutic decision for a patient. As in many other disease processes this estimation is difficult as no single observation or variable is precise in predicting mortality. Therefore, one may use a combination of factors to determine the probability of survival. Utilizing the New York Heart Association (NYHA) functional classification, patients with left ventricular dysfunction are assigned to one of the groups based on their symptoms. The classification of patients by their symptomatology has prognostic value (i.e. Class I > Class IV survival). CLASS I No limitation, ordinary physical activity does not produce symptoms of heart failure. CLASS II Slight limitation of physical activity with no symptoms at rest; symptoms provoked by ordinary physical activity. CLASS III Marked limitation of physical activity with no symptoms at rest; symptoms provoked by less-than-ordinary physical activity. CLASS IV Inability to carry on any physical activity without symptoms. Symptoms present at rest. Left ventricular function. Left ventricular (LV) ejection fraction is a prognostic factor for patient populations such as the survivors of myocardial infarction, but is less useful once heart failure has progressed to NYHA Class III or IV symptoms. For example, an ejection fraction over 30% is associated with better survival, but once below 30%, there is little